Abstract
Background:
Gemcitabine (GEM) is a first-line chemotherapy for bladder cancer (BCa), but its efficacy is limited by drug resistance and side effects. Ursolic acid (UA), a natural compound from medicinal herbs, has shown potential to enhance chemotherapy. This study investigates whether UA synergizes with GEM against BCa and explores the underlying mechanisms.
Methods:
Human BCa cell lines (T24 and 5637) were treated with GEM and/or UA in vitro. Cell viability was assessed via Cell Counting Kit-8 (CCK-8) assay; apoptosis was evaluated using Hoechst 33258 staining, flow cytometry, and western blotting. A xenograft mouse model was employed for in vivo validation. Signaling pathways [phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT), c-Jun N-terminal kinase (JNK)] were analyzed by western blot. Pharmacological modulators (SC79, SP600125) were used to verify pathway roles.
Results:
UA synergistically enhanced GEM's antitumor effects in BCa cells, significantly reducing viability and increasing apoptosis compared to GEM alone. In vivo, UA potentiated GEM's growth inhibition in xenografts. Mechanistically, UA augmented GEM-induced apoptosis by suppressing PI3K/AKT and activating JNK signaling pathways in vitro and in vivo. Both SC79 (AKT activator) and SP600125 (JNK inhibitor) attenuated apoptosis markers (cleaved PARP, cleaved caspase-3).
Conclusions:
UA sensitizes BCa to GEM chemotherapy by promoting apoptosis, mediated through PI3K/AKT inactivation and JNK activation. These findings highlight UA as a promising adjunct to GEM therapy, warranting further clinical exploration.
Keywords:
Ursolic acid (UA); bladder cancer (BCa); c-Jun N-terminal kinase (JNK); gemcitabine (GEM); phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT).